Novel immunotherapies for melanoma are having a major clinical impact. However, the mechanisms that explain why a subset of patients responds to these therapies while other patients do not remain incompletely understood. Our preliminary data suggest that a baseline T cell-inflamed tumor microenvironment may be a predictive biomarker for response to multiple immunotherapies. Our over-arching hypothesis is that germline polymorphisms in the host along with molecular features of the tumor cells profoundly influence the extent of a spontaneous T cell response against a patient's melanoma, which in turn will determine the likelihood of response to therapy. In Specific Aim 1, germline polymorphisms and somatic changes in the tumor associated with the presence or absence of the T cell-inflamed tumor microenvironment will be identified and characterized. Candidate tumor antigen identification driven by somatic point mutations in the two phenotypes will be pursued. In Specific Aim 2, identified genetic variants will be analyzed prospectively as candidate molecular markers for clinical activity with anti-PD-1 therapy. In Specific Aim 3, mechanistic experiments will be performed to understand how identified host gene variants and tumor somatic changes regulate anti-tumor immune responses and T cell infiltration into tumors. At the conclusion of these studies, a deeper understanding the molecular mechanisms that govern the generation of the T cell-inflamed tumor microenvironment as a proximal phenotype will point towards additional key molecular targets for therapy, but in addition will offer predictve biomarkers for clinical response to the most active new therapeutic agents.